Journal article
A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility
Antimicrobial agents and chemotherapy, v 52(7), pp 2305-2312
Jul 2008
PMID: 18443110
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Candida parapsilosis
has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting.
C. parapsilosis
is part of a closely related group of organisms that includes the species
Candida orthopsilosis
and
Candida metapsilosis
. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other
Candida
species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the
C. parapsilosis
group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from
C. albicans
. Furthermore, clinical isolates of
C. albicans
and
C. glabrata
which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced
V
max
values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for
C. parapsilosis
group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of
Saccharomyces cerevisiae
. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the
C. parapsilosis
group accounts for the reduced susceptibility phenotype.
Metrics
Details
- Title
- A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility
- Creators
- Guillermo Garcia-Effron - Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New JerseySantosh K Katiyar - Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New JerseySteven Park - Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New JerseyThomas D Edlind - Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New JerseyDavid S Perlin - Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
- Publication Details
- Antimicrobial agents and chemotherapy, v 52(7), pp 2305-2312
- Publisher
- American Society for Microbiology (ASM)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000257183400003
- Scopus ID
- 2-s2.0-46249106060
- Other Identifier
- 991014877659404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy